The role played by stereochemistry in the C2-substituent (left part) on the S-DABO scaffold for anti-HIV-1 activity has been investigated for the first time. A series of S-DABO analogues, where the double bond in the C2-substituent is replaced by an enantiopure isosteric cyclopropyl moiety, has been synthesized, leading to the identification of a potent lead compound endowed with picomolar activity against RT (wt) and nanomolar activity against selected drug-resistant mutants. Molecular modeling calculation, enzymatic studies, and surface plasmon resonance experiments allowed us to rationalize the biological behavior of the synthesized compounds, which act as mixed-type inhibitors of HIV-1 RT K103N, with a preferential association to the enzyme-substrate complex. Taken together, our data show that the right combination of stereochemistry on the left and right parts (C6-substituent) of the S-DABO scaffold plays a key role in the inhibition of both wild-type and drug-resistant enzymes, especially the K103N mutant.
Discovery of Chiral Cyclopropyl Dihydro-Alkylthio-Benzyl-Oxopyrimidine (S-DABO) Derivatives as Potent HIV-1 Reverse Transcriptase Inhibitors with High Activity Against Clinically Relevant Mutants / Marco Radi;Giovanni Maga;Maddalena Alongi;Lucilla Angeli;Alberta Samuele;Samantha Zanoli;Luca Bellucci;Andrea Tafi;Gianni Casaluce;Gianluca Giorgi;Mercedes Armand-Ugon;Emmanuel Gonzalez;José A. Esté;Mireille Baltzinger;Guillaume Bec;Philippe Dumas;Eric Ennifar;Maurizio Botta. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 52(2009), pp. 840-851. [10.1021/jm801330n]